This is a resubmission seeking renewal of a 20-year program encompassing 5 sub-projects which investigate mechanisms and implications of various responses to hypoxia. Three of these continue a long standing line of investigation concerning the pulmonary circulation-the development of vasoconstriction and pulmonary hypertension in response to hypoxia. The proposed studies explore direct effects of hypoxia on pulmonary vascular endothelium and smooth muscle, genetic determinants, and the role of the adventitial fibroblasts in the development of hypoxic pulmonary hypertension. Other projects propose to investigate the ventilatory response to hypoxia and its modulation by genetic factors and the effect of hypoxia on systemic vascular response to pregnancy. There is considerable cross-talk amongst these projects with respect to common underlying scientific principles, shared expertise and resources. Information resulting from these studies should provide insights into the effects of hypoxia on the pulmonary circulation, ventilatory control, and systemic circulatory changes in pregnancy.